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TitleBasis for selective drug evasion of an aminoglycoside-resistance ribosomal RNA modification.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7992, Year 2025
Publish dateAug 27, 2025
AuthorsDebayan Dey / Jacob M Mattingly / Natalia Zelinskaya / Christine M Dunham / Graeme L Conn /
PubMed AbstractAminoglycosides disrupt the fidelity of bacterial protein synthesis, but their potent antibacterial activity is threatened by multiple resistance mechanisms, including methylation of their ribosomal ...Aminoglycosides disrupt the fidelity of bacterial protein synthesis, but their potent antibacterial activity is threatened by multiple resistance mechanisms, including methylation of their ribosomal RNA (rRNA) binding site. However, the impact of one such resistance-conferring methylation on N1 of helix 44 nucleotide A1408 (mA1408) is highly variable with some aminoglycosides retaining significant potency. Here, we examine bacterial susceptibility to diverse aminoglycosides, determine high-resolution electron cryomicroscopy structures of mA1408-modified 70S ribosome-aminoglycoside complexes, and perform molecular dynamics simulations to decipher the key determinants of such "resistance evasion." Collectively, these analyses reveal how some aminoglycosides adapt their conformation to accommodate mA1408, including the roles of specific ring substituents, balancing ligand strain and maintaining favorable interactions, as well as interactions made by additional functional groups that compensate for those disrupted by the modification. This work provides design principles that can guide future rational development of aminoglycosides refractory to resistance conferred by rRNA modifications.
External linksNat Commun / PubMed:40866347 / PubMed Central
MethodsEM (single particle)
Resolution2.2 - 2.7 Å
Structure data

44192

9b4z

EMDB-44192, PDB-9b4z:
E. coli 70S ribosome complex (N1-methylated 16S A1408 + arbekacin)
Method: EM (single particle) / Resolution: 2.2 Å

44193

9b50

EMDB-44193, PDB-9b50:
E. coli 70S ribosome complex (unmethylated 16S A1408 + arbekacin)
Method: EM (single particle) / Resolution: 2.7 Å

44194

9b51

EMDB-44194, PDB-9b51:
E. coli 70S ribosome complex (N1-methylated 16S A1408 + G418)
Method: EM (single particle) / Resolution: 2.4 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-84G:
Arbekacin / antibiotic*YM

ChemComp-ZN:
Unknown entry

ChemComp-GET:
GENETICIN / antibiotic*YM

Source
  • escherichia coli (E. coli)
KeywordsRIBOSOME / aminoglycoside / A1408 / resistance

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